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Aims The purpose of this in vivo human study was to assess the effect of altered gastric emptying and gastrointestinal motility on the absorption of metformin in healthy subjects. Methods An open-label, three treatment, three period crossover study was conducted in 11 healthy volunteers. Each subject received 550 mg metformin hydrochloride in solution alone; 5 min after a 10 mg i.v. dose of metoclopramide; and 30 min after a 30 mg oral dose of propantheline. Metformin solution was radiolabeled by the addition of 99m Tc-DTPA. The gastrointestinal transit of the solution was monitored by gamma scintigraphy and the pharmacokinetic data were correlated with the scintigraphic ®ndings. Results Scintigraphic data indicated that pretreatment with metoclopramide decreased gastric emptying time and increased gastrointestinal motility while pretreatment with propantheline had the opposite effect. The systemic disposition of metformin was not altered by pretreatment with metoclopramide and propantheline, as judged by unchanged renal clearance and elimination half-life of metformin. Extent of metformin absorption was essentially unchanged after pretreatment with metoclopramide. However, AUC(0,?) and % UR (percent dose excreted unchanged in urine) generally increased with increase in gastric emptying time and small intestinal transit times. GI overlay plots showed that the absorption phase of metformin plasma pro®le always coincided with gastric emptying and the beginning of decline of metformin plasma concentrations was usually associated with the colon arrival. Only in cases where the intestinal transit was drastically prolonged by propantheline pretreatment, was a decline in plasma levels observed prior to colon arrival. Conclusions Metformin is primarily absorbed from the small intestine. The extent of metformin absorption is improved when the gastrointestinal motility is slowed. These ®ndings have signi®cant implications in the design of a metformin modi®ed release dosage form.

Nefazodone is a new antidepressant drug, chemically unrelated to the tricyclic, tetracyclic or selective serotonin uptake inhibitors. Nefazodone blocks the serotonin 5-HT2 receptors and reversibly inhibits serotonin reuptake in vivo. Nefazodone is completely and rapidly absorbed after oral administration with a peak plasma concentration observed within 2 hours of administration. Nefazodone undergoes significant first-pass metabolism resulting in an oral bioavailability of approximately 20%. Although there is an 18% increase in nefazodone bioavailability with food, this increase is not clinically significant and nefazodone can be administered without regard to meals. Three pharmacologically active nefazodone metabolites have been identified: hydroxy-nefazodone, triazoledione and m-chlorophenylpiperazine (mCPP). The pharmacokinetics of nefazodone are nonlinear. The increase in plasma concentrations of nefazodone are greater than would be expected if they were proportional to increases in dose. Steady-state plasma concentrations of nefazodone are attained within 4 days of the commencement of administration. The pharmacokinetics of nefazodone are not appreciably altered in patients with renal or mild-to-moderate hepatic impairment. However, nefazodone plasma concentrations are increased in severe hepatic impairment and in the elderly, especially in elderly females. Lower doses of nefazodone may be necessary in these groups. Nefazodone is a weak inhibitor of cytochrome P450 (CYP) 2D6 and does not inhibit CYP1A2. It is not anticipated that nefazodone will interact with drugs cleared by these isozymes. Indeed, nefazodone did not affect the pharmacokinetics of theophylline, a compound cleared by CYP1A2. Nefazodone is metabolised by and inhibits CYP3A4. Clinically significant interactions have been observed between nefazodone and the benzodiazepines triazolam and alprazolam, cyclosporin and carbamazepine. The potential for a clinically significant interaction between nefazodone and other drugs cleared by CYP3A4 (e.g. terfenadine) should be considered before the coadministration of these compounds. There was an increase in haloperidol plasma concentrations when coadministered with nefazodone; nefazodone pharmacokinetics were not affected after coadministration. No clinically significant interaction was observed when nefazodone was administered with lorazepam, lithium, alcohol, cimetidine, warfarin, theophylline or propranolol.

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Tazobactam is an irreversible inhibitor of many beta-lactamases. In combination with piperacillin, tazobactam exhibits synergy against many beta-lactamase-producing bacteria. The pharmacokinetics of piperacillin and tazobactam were evaluated in eight normal volunteers and in 52 patients with renal dysfunction. Plasma and urine were obtained for up to 30 hours after an infusion of piperacillin and tazobactam (3 and 0.375 gm, respectively). Dialysate samples were collected from patients undergoing dialysis. Piperacillin and tazobactam concentrations were determined by high-performance liquid chromatography. Noncompartmental methods were used for pharmacokinetic analysis. Piperacillin and tazobactam total body clearance, area under the curve, and terminal elimination rate correlated with renal function. Hemodialysis removed 31% and 39% of piperacillin and tazobactam, respectively. During continuous ambulatory peritoneal dialysis, 5.5% of the piperacillin and 10.7% of the tazobactam was recovered in the dialysate over 28 hours. Peak plasma concentrations of both drugs increased minimally with decreasing creatinine clearance. Dosage alterations for creatinine clearance values less than 40 ml/min are recommended.